A meta-analysis on the uncinate fasciculus in depression

Abstract

Aberrant microstructure of the uncinate fasciculus (UNC), a white matter (WM) tract implicated in emotion regulation, has been hypothesized as a neurobiological mechanism of depression. However, studies testing this hypothesis have yielded inconsistent results. The present meta-analysis consolidates evidence from 44 studies comparing fractional anisotropy (FA) and radial diffusivity (RD), two metrics characterizing WM microstructure, of the UNC in individuals with depression (n = 5016) to healthy individuals (n = 18 425). We conduct meta-regressions to identify demographic and clinical characteristics that contribute to cross-study heterogeneity in UNC findings. UNC FA was reduced in individuals with depression compared to healthy individuals. UNC RD was comparable between individuals with depression and healthy individuals. Comorbid anxiety explained inter-study heterogeneity in UNC findings. Depression is associated with perturbations in UNC microstructure, specifically with respect to UNC FA and not UNC RD. The association between depression and UNC microstructure appears to be moderated by anxiety. Future work should unravel the cellular mechanisms contributing to aberrant UNC microstructure in depression; clarify the relationship between UNC microstructure, depression, and anxiety; and link UNC microstructure to psychological processes, such as emotion regulation.

Keywords: comorbid anxiety; depression; first-degree relatives; fractional anisotropy; radial diffusivity; uncinate fasciculus; white matter.

Figure 1.

Flow chart of the literature search process. Abbreviations: FA, fractional anisotropy; HC, healthy controls; MDD, major depressive disorder; NOS, Newcastle-Ottawa Assessment Scale; REL, first-degree relatives; TOI, tract-of-interest; UNC, uncinate fasciculus. Note: *One study (Liu et al., 2021) compared UNC FA between MDD and HC as well as REL and HC.

Figure 2.

Tract-of-interest meta-analysis comparing fractional anisotropy in the uncinate fasciculus between individuals with depression and healthy controls. Here, the left uncinate fasciculus (in orange) and right uncinate fasciculus (in red) are depicted. These tracts interconnect the amygdala (in green) to the orbitofrontal cortex (in blue). (a) Forest plots, with the black diamond representing the overall effect size of each study. (b) Funnel plots, with the dotted line representing the overall effect size. Symmetric funnel plots indicate an absence of publication bias, with a majority of studies falling in the area of statistical non-significance (p > 0.1). The five most extreme points on each funnel plot are labeled with the study author and year. Abbreviations: CI, confidence interval; FA, fractional anisotropy; RE model, random-effect model; SE, standard error.